Current topics in microbiology and immunology最新文献

Epstein-Barr virus (EBV) is a potent oncogenic virus capable of manipulating cell death and cell survival pathways in order to persist in human B cells. Since the discovery of EBV in Burkitt's lymphoma cells in 1964, cell culture has played an important role in uncovering EBV's ability to overcome cell death pathways such as apoptosis and ferroptosis. Whilst apoptosis is a genetically defined and developmentally regulated non-immunogenic cell death program, ferroptosis is a mode of necrotic cell death that is closely linked to amino acid, lipid, redox, energy, selenium, and iron metabolism. Such cell culture studies have not only played a pivotal role in our understanding of the role of EBV in growth transformation and cancer but have also enriched knowledge in the fields of cell death. Artificial in vitro cell culture conditions including (i) oxygen partial pressure, (ii) media composition, (iii) cell density, (iv) cell-, and (v) pH-homo- versus heterogeneity have profound effects on cell growth and responses to death stimuli. In fact, a search for pro-survival genes in Burkitt's lymphoma cells plated at low cell density in FCS-supplemented RPMI 1640 medium had revealed two genes, glutathione peroxidase-4 (GPX4) and ferroptosis-suppressor protein-1 (FSP1), that are now well-known master regulators protecting cells from ferroptosis. Here we review those early fundamental studies and reflect on the subsequent literature that seeks to understand how EBV viral products can modulate cellular pathways during transformation and oncogenesis, reducing the requirement for mutations in cellular genes that are found more commonly in EBV-negative Burkitt's lymphomas.

Cell migration is an enormously complex process that requires sophisticated regulation and exquisite coordination of many cellular proteins that must act in a temporally and spatially orchestrated manner to achieve directional motion. Much like neuromuscular control of gait and walking, except within a single cell, a series of rapid feedback mechanisms must act in a cyclical manner to result in movement. The protein-serine kinase Akt/PKB that acts downstream of phosphatidylinositol 3' kinase (PI3K) activation is intricately involved in normal cell migration and in aberrant movement (e.g., cancer metastasis), but its role can be either pro- or anti-migration depending on cellular context. These contradictory effects likely reflect the nature of cellular motion, in that perturbations that disturb the continuity or integrity of migratory machines tend to be inhibitory. In contrast, increasing overall efficiency/coordination of the processes results in greater mobility. The net result of modulating Akt/PKB is therefore highly dependent upon other inputs into the cell and their context. Here, we briefly describe the molecular events associated with cellular migration, then describe current knowledge of Akt/PKB targets involved in this process, and conclude by discussing implications for suppression of cancer dissemination.

Burkitt lymphoma (BL) remains a prevalent pediatric cancer in sub-Saharan Africa and was the first human cancer identified with a virus when Epstein-Barr virus (EBV) was discovered in a Ugandan BL tumor in 1964. The impact of EBV in BL is highlighted by a new molecular tumor classification of EBV positivity versus negativity which is starting to supersede longstanding epidemiologic classifications. The high incidence of EBV-positive BL in Africa and Papua New Guinea has been linked to Plasmodium falciparum (Pf) malaria coinfections in young children. Epidemiologic studies have yielded insight into early-age EBV infections and have demonstrated direct impacts of Pf malaria infections on EBV reactivation and disruptions in EBV persistence. Moreover, when children residing in malaria holoendemic regions are contending with chronic Pf malaria infections, they undergo immune adaptations to mitigate life-threatening immunopathology. We postulate that this malaria-induced immune conditioning leads to diminished EBV-specific cellular immune surveillance, when combined with higher B cell proliferation, and EBV load creates a permissive environment for BL tumorigenesis.

LMP2A is the Rodney Dangerfield of viral oncogenes: It gets no respect. Initial impressions-that it was dispensable for EBV transformation of B lymphocytes and only enhanced transformation efficiency-still shape how this oncogene is viewed. This view needs to be reconsidered in light of a wealth of evidence supporting its role as a key oncogene in EBV-associated malignancies. LMP2A constitutively activates the PI3K/Akt/mTOR pathway, the most frequently mutated pathway in human cancer. In nasopharyngeal and gastric carcinomas, which account for most EBV-associated cancers, LMP2A is expressed much more frequently than LMP1 and is a dependency factor in both malignancies. Additionally, as a B cell receptor (BCR) mimic, LMP2A plays an essential role in EBV's persistence strategy of establishing life-long infection in memory-like B cells by mimicking germinal center reactions and maintaining EBV latency. Finally, recent studies suggest that LCLs are dependent on LMP2A signaling and ΔLMP2A-LCLs are phenotypically distinct from wildtype LCLs. As we seek to define EBV's role in autoimmunity, it will be important to understand the extent to which LMP2A contributes to these diseases as well. As a constitutive BCR mimic, LMP2A may drive aberrant B cell activation and survival, potentially promoting the breakdown of tolerance. We should be cautious not to underestimate its role in autoimmunity as was once done in cancer.

EBV expresses multiple viral noncoding RNAs (ncRNAs) throughout infection with regulatory activities that influence critical stages of the viral life cycle, including the establishment of latent infection and reactivation from latency. Advances in RNA sequencing technologies continue to reveal novel and diverse types of ncRNAs produced by EBV. Among these are the EBV-encoded RNAs (EBERs), the BamHI A rightward transcripts (BARTs), circular RNAs (circRNAs), stable intronic (sis) RNAs, lytic-associated ncRNAs, and viral microRNAs (miRNAs). While exact functions for most EBV ncRNAs are not fully resolved, multiple studies reveal important roles for these molecules in mediating essential aspects of the viral life cycle such as modulation of viral gene expression, cell survival, and immune evasion. This chapter updates our current knowledge of the different types of ncRNAs encoded by EBV and how these molecules critically contribute to viral persistence and disease.

The new era of microbial cell death stems from a flood of new information emanating from the mechanistic and evolutionary life sciences, philosophy, and even sociology. In the shifting landscape, longstanding cell death terminologies and concepts have rightfully been questioned. There is currently very little consensus on how these concepts should be defined. One result of this is that similar findings often prompt different explanations because of the diversity of meanings associated with the terms. In this chapter, we review terms and concepts in microbial cell death that are key to understanding cell mortality. We discuss concepts like cell death, mortality, and the distinction between endogenous and exogenous death. We examine the contentious problem of defining programmed cell death (PCD) and argue that an evolutionary concept of PCD is foundational and applies to all cells across the tree of life, including microbial taxa. Alternative conceptions that define PCD in mechanistic, developmental, and ecological terms are useful tools for dissecting the molecular mechanisms, environmental triggers, and functions of PCD, but they do not define what PCD fundamentally is. Finally, we emphasize the importance of being clear on such concepts in order to achieve an overarching cell mortality framework.

Classical Hodgkin lymphoma (cHL) is a unique B cell malignancy characterised by the presence of Hodgkin/Reed-Sternberg (HRS) cells within an extensive inflammatory microenvironment. In approximately 40% of cases- particularly in the mixed cellularity subtype-HRS cells are infected with the Epstein-Barr virus (EBV). EBV-positive cHL displays a restricted pattern of viral gene expression (latency II), with functional contributions from EBNA1, LMP1, and LMP2A/B, as well as some non-coding RNAs. This review synthesises current knowledge on the role of EBV in the pathogenesis of cHL. It provides an overview of molecular and immunological distinctions between EBV-positive and EBV-negative cHL, highlighting differences in host genomic alterations, immune evasion strategies, and tumour microenvironment composition. EBV+ cHL demonstrates a relatively lower mutational burden but harnesses viral proteins to subvert immune surveillance, recruit regulatory immune subsets, and upregulate checkpoint ligands, such as PD-L1. We also discuss the prognostic significance of EBV in cHL, its epidemiological associations with HLA polymorphisms, and emerging EBV-directed immunotherapies- including virus-specific T cell transfer and engineered TCR approaches.

Epstein Barr virus (EBV) was discovered 60 years ago as the first candidate human tumor virus. Since then, we have realized that this human γ-herpesvirus establishes persistent infection in the majority of adult humans but fortunately causes EBV associated diseases only in a few individuals. This is an incredible success story of the human immune system, which controls EBV infection and its transforming capacity for decades after initial virus encounter. A better understanding of this immune control would not only benefit patients with EBV associated malignancies but could also provide clues on how to establish such a potent, mostly cell-mediated immune control against other pathogens and tumors. However, the functional relevance of EBV specific immune responses can only be addressed in vivo and mice with reconstituted human immune system components (humanized mice) constitute a small animal model that can be infected with EBV, recapitulates some aspects of virus associated tumorigenesis, and mounts mostly cell-mediated immune responses against EBV. This chapter will summarize the insights into EBV immunobiology that have already been gained in humanized mouse models and provide an outlook into promising future avenues to further characterize EBV infection, immune control, and associated pathologies in vivo.

More than 500 primary immunodeficiencies (PIDs) or inborn errors of immunity (IEIs) have been reported. In general, IEIs are caused by monogenic germinal variants resulting in immunodeficiency and immune dysregulation symptoms. These "in natura" experiments have highlighted selective factors and pathways required for the immune control of a given pathogen, including Epstein-Barr virus (EBV). Several IEIs predominantly predispose to develop severe EBV infections and associated diseases including infectious mononucleosis (IM), hemophagocytic lymphohistiocytosis (HLH) and nonmalignant or malignant B cell lymphoproliferative disorders (B-LPD). Identification of these IEIs revealed critical components/molecules of the immune response to EBV. Notably, these elements differ depending on the type of the EBV viral disease. On one hand, defects in factors involved in the cytotoxic responses of lymphocytes preferentially underlie HLH, whereas, on the other hand, factors implicated in the expansion of EBV-specific T cells are mostly responsible for B-LPD when impaired. IEIs also inform on mechanisms underlying rare EBV viral diseases such as EBV⁺ smooth muscle tumors (EBV⁺SMT) and the "atypical" T/NK cell lymphoproliferative disorders (NK/T-LPD) including chronic active EBV infections (CAEBV). Finally, IEIs not predisposing to EBV provide information on immune components not necessary or redundant for EBV immunity. All these aspects are discussed in this chapter.